Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells
Niemann-Pick type C (NPC) disease is a fatal inherited lipid storage disorder causing severe neurodegeneration and liver dysfunction with only limited treatment options for patients. Loss of NPC1 function causes defects in cholesterol metabolism and has recently been implicated in deregulation of au...
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| Format: | Article |
| Language: | en_US |
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Elsevier B.V.
2015
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| Online Access: | http://hdl.handle.net/1721.1/96366 https://orcid.org/0000-0001-9724-6776 |
| _version_ | 1826212326255099904 |
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| author | Maetzel, Dorothea Sarkar, Sovan Wang, Haoyi Abi-Mosleh, Lina Xu, Ping Gao, Qing Mitalipova, Maisam Jaenisch, Rudolf Cheng, Albert Wu |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Maetzel, Dorothea Sarkar, Sovan Wang, Haoyi Abi-Mosleh, Lina Xu, Ping Gao, Qing Mitalipova, Maisam Jaenisch, Rudolf Cheng, Albert Wu |
| author_sort | Maetzel, Dorothea |
| collection | MIT |
| description | Niemann-Pick type C (NPC) disease is a fatal inherited lipid storage disorder causing severe neurodegeneration and liver dysfunction with only limited treatment options for patients. Loss of NPC1 function causes defects in cholesterol metabolism and has recently been implicated in deregulation of autophagy. Here, we report the generation of isogenic pairs of NPC patient-specific induced pluripotent stem cells (iPSCs) using transcription activator-like effector nucleases (TALENs). We observed decreased cell viability, cholesterol accumulation, and dysfunctional autophagic flux in NPC1-deficient human hepatic and neural cells. Genetic correction of a disease-causing mutation rescued these defects and directly linked NPC1 protein function to impaired cholesterol metabolism and autophagy. Screening for autophagy-inducing compounds in disease-affected human cells showed cell type specificity. Carbamazepine was found to be cytoprotective and effective in restoring the autophagy defects in both NPC1-deficient hepatic and neuronal cells and therefore may be a promising treatment option with overall benefit for NPC disease. |
| first_indexed | 2024-09-23T15:19:56Z |
| format | Article |
| id | mit-1721.1/96366 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:19:56Z |
| publishDate | 2015 |
| publisher | Elsevier B.V. |
| record_format | dspace |
| spelling | mit-1721.1/963662022-10-02T02:12:50Z Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells Maetzel, Dorothea Sarkar, Sovan Wang, Haoyi Abi-Mosleh, Lina Xu, Ping Gao, Qing Mitalipova, Maisam Jaenisch, Rudolf Cheng, Albert Wu Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Maetzel, Dorothea Sarkar, Sovan Wang, Haoyi Xu, Ping Cheng, Albert W. Gao, Qing Mitalipova, Maisam Jaenisch, Rudolf Niemann-Pick type C (NPC) disease is a fatal inherited lipid storage disorder causing severe neurodegeneration and liver dysfunction with only limited treatment options for patients. Loss of NPC1 function causes defects in cholesterol metabolism and has recently been implicated in deregulation of autophagy. Here, we report the generation of isogenic pairs of NPC patient-specific induced pluripotent stem cells (iPSCs) using transcription activator-like effector nucleases (TALENs). We observed decreased cell viability, cholesterol accumulation, and dysfunctional autophagic flux in NPC1-deficient human hepatic and neural cells. Genetic correction of a disease-causing mutation rescued these defects and directly linked NPC1 protein function to impaired cholesterol metabolism and autophagy. Screening for autophagy-inducing compounds in disease-affected human cells showed cell type specificity. Carbamazepine was found to be cytoprotective and effective in restoring the autophagy defects in both NPC1-deficient hepatic and neuronal cells and therefore may be a promising treatment option with overall benefit for NPC disease. National Niemann-Pick Disease Foundation (Peter G. Pentchev Research Fellow) University of Cambridge (Hughes Hall fellow) National Institutes of Health (U.S.) (US NIH grant R01- CA084198) MIT Skoltech Initiative National Institutes of Health (U.S.) (US NIH grant HL20948) 2015-04-03T13:48:59Z 2015-04-03T13:48:59Z 2014-06 2014-03 Article http://purl.org/eprint/type/JournalArticle 22136711 http://hdl.handle.net/1721.1/96366 Maetzel, Dorothea, Sovan Sarkar, Haoyi Wang, Lina Abi-Mosleh, Ping Xu, Albert W. Cheng, Qing Gao, Maisam Mitalipova, and Rudolf Jaenisch. “Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells.” Stem Cell Reports 2, no. 6 (June 2014): 866–880. https://orcid.org/0000-0001-9724-6776 en_US http://dx.doi.org/10.1016/j.stemcr.2014.03.014 Stem Cell Reports Creative Commons Attribution http://creativecommons.org/licenses/by-nc-nd/3.0/ application/pdf Elsevier B.V. Elsevier |
| spellingShingle | Maetzel, Dorothea Sarkar, Sovan Wang, Haoyi Abi-Mosleh, Lina Xu, Ping Gao, Qing Mitalipova, Maisam Jaenisch, Rudolf Cheng, Albert Wu Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells |
| title | Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells |
| title_full | Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells |
| title_fullStr | Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells |
| title_full_unstemmed | Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells |
| title_short | Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells |
| title_sort | genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from niemann pick type c patient specific ips cells |
| url | http://hdl.handle.net/1721.1/96366 https://orcid.org/0000-0001-9724-6776 |
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